Sci. Aging Knowl. Environ., 18 June 2003
Vol. 2003, Issue 24, p. nw88
[DOI: 10.1126/sageke.2003.24.nw88]


Keeping Out the Riffraff

New strategy might lock Alzheimer's protein out of the brain

Mitch Leslie;2003/24/nw88

Key Words: low-density lipoprotein receptor-related protein • endothelin • tumor necrosis factor

The blood-brain barrier acts as the brain's bouncer: It prevents trouble by barring unsavory characters. A new study reveals that a particular protein ushers {beta} amyloid, a blood-borne peptide that piles up in Alzheimer's disease, past the barrier. The work suggests that thwarting the protein might slam the door on {beta} amyloid and slow its buildup in the brain.

Globs of {beta} amyloid form plaques that jam the brains of patients with Alzheimer's disease (AD), and most researchers think that it provokes at least some of the illness's insidious effects (see "Detangling Alzheimer's Disease"). Scientists have focused on how {beta} amyloid damages neurons, says neurovascular biologist Berislav Zlokovic of the University of Rochester Medical Center in New York, but it also spurs inflammation and reduces blood flow to the brain, triggering "silent strokes." All body cells make {beta} amyloid, which is able to travel in the blood and cross into the brain, where it might contribute to AD plaques. But {beta} amyloid needs help to crash the blood-brain barrier in large quantities. Recent studies hinted that a molecule called the receptor for advanced glycation end products (RAGE), which protrudes into the bloodstream from cells that line small vessels in the brain, shuttles {beta} amyloid across the barrier. RAGE attaches to {beta} amyloid, and brain tissue samples from AD patients tote extra RAGE.

To pin down RAGE's role, Zlokovic and colleagues injected radioactively labeled {beta} amyloid into the bloodstream of mice and measured how much of it the brain absorbed. Adding an antibody that blocked RAGE cut {beta} amyloid uptake by 70%. And in mice engineered to lack the receptor, almost no {beta} amyloid entered the brain. The researchers then determined whether meddling with RAGE could reduce {beta}-amyloid buildup in mice engineered to rapidly accumulate the protein. They dosed some of the mice with free-floating RAGE, which grabs {beta} amyloid, preventing it from consorting with RAGE in vessel walls and entering the brain. Compared with controls, the treated mice carried less than 30% as much {beta} amyloid in their brains, and their plaque deposits were 78% smaller, indicating that the treatment had barred {beta} amyloid from the brain. The researchers next measured the effect of blocking RAGE in a line of engineered mice that suffer from AD-like symptoms, including reduced blood flow to the brain. Injections of RAGE or antibodies against RAGE hiked blood flow 60%. The findings suggest that compounds that obstruct RAGE might squelch the buildup of {beta} amyloid in the human brain and quell AD symptoms by increasing blood supply, says Zlokovic.

The study is "a major advance" in understanding the transportation of {beta} amyloid, says AD expert George Perry of Case Western Reserve University in Cleveland, Ohio. Neuroscientist Mark Smith, also at Case Western, agrees. Testing whether blocking RAGE eases symptoms in people is the next step, he says; "that's an exciting possibility." Such research might reveal whether scientists will be able to coax the brain's bouncer to cross {beta} amyloid off the guest list.

--Mitch Leslie; suggested by Amir Sadighi Akha

June 18, 2003
  1. R. Deane et al., RAGE mediates amyloid-{beta} peptide transport across the blood-brain barrier and accumulation in the brain. Nat. Med., 15 June 2003 [e-pub ahead of print]. [Abstract/Full Text]
Citation: M. Leslie, Keeping Out the Riffraff. Sci. SAGE KE 2003, nw88 (18 June 2003);2003/24/nw88

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